FIELD OF THE INVENTION
The present invention relates to an iontophoretic patch for the transdermal delivery of drugs, with an improved hydrogel reservoir.
Administration of medicaments using iontophoresis is known. Simply defined, iontophoresis is the introduction by means of electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes. In presently known iontophoretic devices, at least two electrodes are used. Both of these electrodes are positioned to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be delivered into the body is positively charged, i.e. a cation, then the anode will be the active electrode and the cathode will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, i.e. an anion, then the cathode will be the active electrode and the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the anode can deliver a positively charged ionic substance into the body while the cathode can deliver a negatively charged ionic substance into the body.
It is also known that iontophoretic delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process called electroosmosis. Electroosmosis is transdermal flux of a liquid solvent (e.g., the liquid solvent containing the uncharged drug or agent) which is induced by the presence of an electric field imposed across the skin by the donor electrode. As used herein, the terms "iontophoresis" and "iontophoretic" apply equally to electrically powered devices which deliver charged/ionic agents by iontophoresis as well as to electrically powered devices which deliver uncharged/nonionic agents by electroosmosis.
In the typical iontophoretic patch, a matrix of reservoirs to hold the drug or medicament, or beneficial agent is provided. A reservoir can be of any material adapted to absorb and hold a sufficient quantity of liquid therein in order to permit transport of agent therethrough by iontophoresis. Preferably, a matrix of reservoirs is used, which is composed at least in part of a hydrophilic polymer.
In order to conduct electrical current the reservoirs must be sufficiently hydrated to allow ions to flow therethrough. In most cases the liquids used to hydrate the matrices of the reservoirs will be water, but other liquids can also be used to activate the matrices of the reservoirs.
The combination of water soluble polymer and water or liquid results in the reservoir containing a hydrogel. Electrical current is applied to the reservoir by means of a current distributing member. This member can take the form of a metal plate, a foil layer, a screen or a dispersion of particles. Use of sacrificial current distributing members which are oxidized or reduced during drug delivery are preferred. However, such devices produce ions, such as silver ions, which cannot be permitted to be transferred to the skin due to adverse affects. Nor can a significant build-up of ions be permitted because the efficiency of the iontophoresis device may be impeded due to competition with the drug ion.
Therefore it is necessary for the reservoir also to contain a counter-ion to react with the electrochemically generated ion. However, many drug salts do not possess the proper ion for reacting with the electrochemically generated ion. For example, in some instances, water soluble salts would be produced, which would remain in their ionized state in the reservoir. Therefore, it is important to provide a counter-ion in the reservoir which can effectively eliminate the ion generated by the electrode.
Since the drug to be delivered is also charged, precautions must be taken to prevent the drug from coming into contact with counter-ions which are incorporated to eliminate the ion generated by the electrode. Methods of accomplishing this are known in the art. A two compartment model is typically used, comprising a drug reservoir which must be isolated from the second reservoir containing the active electrode by a membrane that prevents direct contact between the drug and the ion exchange media.
Membranes, typically size exclusion membranes, are used to separate the two reservoir compartments. The membrane must be selected to prevent the drug ion from migrating into the reservoir containing the active electrode, and also to prevent the ion exchange means from drifting into the drug reservoir. An example of such a two compartment device is shown in FIG. 1. A two compartment reservoir 1, is divided into an upper reservoir 2 containing an active electrode 3. The reservoirs are situated in a foam ring 6. The upper reservoir is separated from a lower reservoir 4 by a separator membrane 5. In this instance the drug is stored in the lower reservoir. The bottom of the lower reservoir is sealed by a release liner 7, which is removed prior to application of the iontophoretic device to a patient. Examples of other two compartment membranes may be found in Haak, U.S. Pat. No. 4,927,408 and Phipps, U.S. Pat. No. 5,084,008.
In Phipps, it is the drug containing reservoir which is equipped with the counter ion. In one embodiment, this is accomplished by constructing an electrode having a conductive, current distributing member; means for coupling the current distributing member to a source of electrical current; a reservoir containing an ionic or ionizable drug; an ion source layer in intimate contact with the current distributing member; and a layer of selectively permeable material applied to the ion source layer which is between the current distributing member and the reservoir. Examples of ion source layers include salt layers, ion exchange resins or chelating agents. Also useful are salts in thin hydrogel material or a substantially dehydrated layer which would absorb a solvent. The selectively permeable material is capable of separating materials by charge and/or size. The construction of this device is complex, involving many different layers, thus increasing the cost and time for their manufacture.
Haak discloses a construction where the drug reservoir is in contact with a membrane, including a hydrogel, which is loaded with an ion exchange resin or a chelating agent. However, such a device brings the drug into contact with ion exchange media, such as a membrane or resin, and this can lead to some portion of the drug becoming immobilized. Further, restricting the ion exchange capacity of the device to a thin membrane, rather than a large volume of material, limits its ion exchange capacity.
Phipps U.S. Pat. No. 5,423,739 discloses a two layer iontophoretic device, wherein the top layer is referred to as the carrier layer and the bottom layer is the skin-contacting layer. The skin contacting layer contains an ionic polymer component. In Phipps, the carrier layer includes the drug or active agent, and few or no mobile ionizable substances. In one embodiment, the mobile ions of the hydrogel in the skin contacting layer have a charge opposite from that of the ionized active agent. This means that the ionized active agent and the polymer backbone have the same charge. The two layers are separated by an impermeable carrier and the device only becomes active when this impermeable barrier is breached. Once the impermeable barrier is broken, the ionized active agent and the mobile counter ions are in direct contact with each other. This contact can lead to unwanted interaction between these two elements and adversely affect drug delivery.
Phipps also suggests that the relatively small counter ion of the ionomeric component in the skin contacting layer can be selected to interact with the electrochemically generated species at the anode or the cathode. However, this arrangement relies on the mobile counter ions being able to come into contact with the electrochemically generated ions in a very complex matrix system. Due to the complexities of various hydrogel systems, one cannot always be assured that the mobile counter ions will encounter and react with the electrochemically generated ions. Further, the unwanted interactions between the ionized active agent and the mobile counter ion also exist in this arrangement.
Additionally, Phipps shows examples where the active agent and the ionic polymer backbone are oppositely charged. However, in these instances, the active agent and the ionic polymer are in direct contact with each other in order to convert the active agent to a cationic state.
Additionally, the reservoirs containing the active electrode have been known to include water-insoluble, cross-linked ion-exchange resins which serve to bind the ion generated during the iontophoretic process. An example of the use of a non-water soluble ion-exchange resin in a iontophoretic patch reservoir is found in Chien, et al., U.S. Pat. No. 5,250,022.
Ion-exchange resins, which are included in the hydrogel in the reservoir in the prior art, such as those disclosed in Chien, result in the hydrogel reservoir having a non-uniform consistency. The resins often settle out of the matrix. Very high concentrations of ion exchange resin at the bottom of the reservoir can hinder ion mobility, which can seriously affect the operation of the iontophoretic patch.
Uniform reservoirs are also difficult to achieve when processing the ion-exchange resins due to the fact that the cross-linked particles behave as a filler, so viscosity increases hyperbolically with particle concentration. The matrix can often become very dough-like in preparation. This results in production difficulties, and consequently increases the cost of the product, due to lengthy production times and a high rejection rate of finished product. The high viscosity also limits formulation possibilities in designing the drug reservoir.
Ion-exchange membranes, on the other hand, are physical barriers which are not only susceptible to flaws, they can also be damaged, thus potentially greatly diminishing their effectiveness.
It is therefore an object of this invention to produce a hydrogel reservoir matrix for a two compartment iontophoretic patch which is homogeneous and not susceptible to separation.
It is another object of this invention to provide a hydrogel reservoir matrix for a two compartment iontophoretic device which can be processed easily, and which does not have an excessive viscosity.
Yet another object of this invention is a hydrogel reservoir matrix for a two compartment iontophoretic patch which is not dependent on a thin physical barrier for ion exchange.
Higher ion exchange capacity per unit volume in a hydrogel reservoir matrix for an iontophoretic patch is also a desired object of this invention.
Increased reliability of the capture of electrochemically generated ions is another feature of the present invention.